1. Field of the Invention
This invention relates to a polymeric composition that generates nitric oxide, and more particularly to a two dimensional polymer having nitric oxide generating functional groups or compounds including nitric oxide generating functional groups bound to the polymer for generating nitric oxide.
2. Description of the Related Art
It is well known that when blood comes into contact with a surface other than the natural wall of a blood vessel, the activation of certain circulating substances results in the coagulation of the blood. If thrombi are formed on portions of the surface which contact blood flow, there is a risk that the thrombi will be released and cause serious blood circulation disturbances called thrombosis. As a result, extensive investigations have been undertaken over many years to find materials having a reduced tendency to form thrombosis. This area of research has become increasingly important with the development of various objects and articles which can be in contact with blood, such as artificial organs, vascular grafts, probes, cannulas, catheters and the like.
Synthetic polymeric materials have come to the fore as preferred materials for such articles. However, these polymeric materials have the major drawback of being thrombogenic. Accordingly, numerous procedures for rendering a polymeric surface non-thrombogenic have been proposed. (As used herein, “non-thrombogenic” and “antithrombogenic” refer to any material which inhibits thrombus formation on a surface.) One known approach for counteracting thrombogenicity of a polymeric surface has been the use of polymer treatments or polymer coatings that serve to inhibit platelet aggregation on the polymeric surface. For instance, functional groups or compounds that inhibit platelet aggregation may be bound to or imbedded in a polymer matrix, or bound to or imbedded in a polymer coating that is applied to the polymer matrix. Typically, antithrombogenic polymer coatings can also be applied to other materials such as metals and ceramics.
For example, U.S. Pat. No. 5,994,444 reports that nitric oxide inhibits platelet activation and discloses a polymeric material capable of releasing nitric oxide so as to inhibit platelet activation. The polymeric material is stated to be useful for lining blood-contacting surfaces of implantable or extracorporeal medical devices so as to reduce or eliminate the undesired effects of platelet aggregation or thrombogenesis. In a preferred embodiment, the polymeric material is capable of generating, donating or releasing nitric oxide in situ, preferably by producing nitric oxide as a result of a chemical conversion of a nitric oxide donor upon hydration of the polymer matrix. In a particularly preferred embodiment, the polymeric material comprises a biodegradable polymer, such as polylactic acid, that yields at least one degradative product, such as lactic acid, that facilitates the conversion of an acid-labile nitric oxide donor, such as inorganic nitrite, to nitric oxide by serving as either an acid or a reducing agent, or both.
U.S. Pat. No. 5,185,376 also reports that compounds including nucleophile-nitric oxide complexes which possess at least one N2O2− functional group decompose in vivo to release nitric oxide and thereby inhibit platelet aggregation. U.S. Pat. Nos. 5,691,423 and 5,405,919 disclose polymeric compositions including a polymer and these nitric oxide generating N2O2− functional groups.
While these nitric oxide releasing polymers may serve to inhibit platelet aggregation on a surface, the preparation of these polymers can present problems. For instance, the preparation of these polymers often requires the coupling of a nitric oxide releasing functional group to a functional group on the polymer. Typically, these coupling reactions are inefficient for various reasons. One method for increasing the efficiency of these coupling reactions involves synthesizing a polymer having side chains with the necessary functional groups. However, the introduction of side chains on a polymer backbone presents further difficulties. One strategy for introducing side chains to a main chain of a polymer is to add the side chains to the preformed main chain. However, this is generally not satisfactory because of the lack of predictability and reproducibility of stoichiometry, under-derivitization for stearic reasons, difficulty in accessing the interior of the polymer, poor solubility of the polymer, and inefficient coupling reactions. An alternative method for introducing side chains to a main chain of a polymer is to attach the desired side chain to each monomer prior to polymer chain formation. This method is generally more efficient but the subsequent coupling of the monomers often requires activating groups to be attached to one or both coupling sites.
These nitric oxide releasing polymers may also exhibit less than ideal physical properties. For example, the nitric oxide releasing polymer is fairly hard and brittle as a result of the ion formation upon addition of the nitric oxide forming the nitric oxide releasing group (Keefer has defined the nitric oxide releasing groups as diazeniumdiolates). Upon forming a film, the nitric oxide releasing polymer forms a “powdery” surface that is easily removed. Also, the film is easily damaged. Therefore, the coating requires some modification in order to form a proper coating that stays in place upon immersion in an aqueous environment.
Thus, there is a need for an antithrombogenic polymer having nitric oxide generating functional groups and having improved physical properties such that the polymer may reliably adhere to substrate surfaces. Furthermore, there is a need for a process that efficiently prepares a polymer having side chains with a functional group that readily bonds to a nitric oxide generating functional group such that an antithrombogenic polymer may be prepared from the polymer and a compound having a nitric oxide generating functional groups.